Dissecting Adrenal and Behavioral Responses to Stress by Targeted Gene Inactivation in Mice (original) (raw)
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Proceedings of the National Academy of Sciences, 2000
Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic–pituitary–adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic–pituitary–adrenal axis during immunological challenge in the absence of hypothalamic input from CRH. IL-6 receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone levels after bacterial lipo...
Psychoneuroendocrinology, 2014
The aim of the present work was to study the influence of variable stress on the expression of 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) and the neuropeptides corticotropin-releasing hormone (CRH), urocortins 2 and 3(UCN2, UCN3), arginine vasopressin (AVP), oxytocin (OXT) and adenylate cyclase-activating polypeptide (PACAP) in two inbred rat strains: stress hypo-responsive Lewis (LEW) and hyper-responsive Fisher 344 (F344) rats. We found site-specific and strain-dependent differences in the basal and stress-stimulated expression of 11HSD1, CRH, UCN2, UCN3 and PACAP. In LEW rats, stress upregulated 11HSD1 in the prefrontal cortex and lateral amygdala, whereas in F344 rats 11HSD1 was upregulated in the central amygdala and hippocampal CA2 and ventral but not dorsal CA1 region; no effect was observed in the paraventricular nucleus, pituitary gland and adrenal cortex of both strains. The expression of glucocorticoid receptors did not parallel the upregulation of 11HSD1. Stress al...
Neuroscience, 2010
Stress responses are elicited by a variety of stimuli and are aimed at counteracting direct or perceived threats to the well-being of an organism. In the mammalian central and peripheral nervous systems, specific cell groups constitute signaling circuits that indicate the presence of a stressor and elaborate an adequate response. Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in central and peripheral parts of these circuits and has recently been identified as a candidate for regulation of the stress axis. In the present experiments, we tested the involvement of PACAP in the response to a psychological stressor in vivo. We used a restraint paradigm and compared PACAP-deficient mice (PACAP؊/؊) to wild-type controls (PACAP؉/؉). Acute secretion of corticosterone elicited by 1 h of restraint was found to be identical between genotypes, whereas sustained secretion provoked by 6 h of unrelieved restraint was 48% lower in PACAP؊/؊mice. Within the latter time frame, expression of messenger RNA (mRNA) encoding corticotropin-releasing hormone (CRH) was increased in the hypothalamus of wild type, but not PACAP-deficient mice. Expression of the activity-regulated transcription factors Egr1 (early growth response 1) and Fos (FBJ osteosarcoma oncogene) in the hypothalamus was rapidly and transiently induced by restraint in a PACAP-dependent fashion, a pattern that was also found in the adrenal glands. Here, abundance of transcripts encoding enzymes required for adrenomedullary catecholamine biosynthesis, namely TH (tyrosine hydroxylase) and PNMT (phenylethanolamine N-methyltransferase), was higher in PACAP؉/؉ mice after 6 h of unrelieved restraint. Our results suggest that sustained corticosterone secretion, synthesis of the hypophysiotropic hormone CRH in the hypothalamus, and synthesis of the enzymes producing the hormone adrenaline in the adrenal medulla, are controlled by PACAP signaling in the mouse. These findings identify PACAP as a major contributor to the stimulus-secretion-synthesis coupling that supports stress responses in vivo. Published by Elsevier Ltd on behalf of IBRO.
Proceedings of the National Academy of Sciences, 2009
Adaptation to stress in vertebrates occurs via activation of hormonal and neuronal signaling cascades in which corticotropinreleasing hormone (CRH) plays a central role. Expression of brain CRH is subject to strong, brain-region specific regulation by glucocorticoid hormones and neurogenic intracellular signals. We hypothesized that Steroid Receptor Coactivator 1 (SRC-1), a transcriptional coregulator of the glucocorticoid receptor, is involved in the sensitivity of CRH regulation by stress-related factors. In the brains of SRC-1 knockout mice we found basal CRH mRNA levels to be lower in the central nucleus of the amygdala. Hypothalamic CRH up-regulation after chronic (but not acute) stress, as well as region-dependent up-and down-regulation induced by synthetic glucocorticoids, were significantly attenuated compared with wild type. The impaired induction of the crh gene by neurogenic signals was corroborated in AtT-20 cells, where siRNA and overexpression experiments showed that SRC-1 is necessary for full induction of a CRH promoter reporter gene by forskolin, suggestive of involvement of transcription factor CREB. In conclusion, SRC-1 is involved in positive and negative regulation of the crh gene, and an important factor for the adaptive capacity of stress.
Behavioural Brain Research, 2007
Stressors increase corticotropin releasing hormone (CRH) functioning in hypothalamic and frontal cortical brain regions, and thus may contribute to the provocation of anxiety and depressive disorder. As the effects of stressors on these behavioral changes are more pronounced in some strains of mice (e.g., BALB/cByJ) than in others (e.g., C57BL/6ByJ), the present investigation assessed whether acute and chronic stressors would differentially influence CRH receptor immunoreactivity (ir-CRHr) and CRH receptor mRNA expression (CRH 1 and CRH 2 ) in the orbital frontal cortex (OFC) of these strains. An acute noise stressor, and to a greater extent a chronic, variable stressor regimen reduced ir-CRHr in BALB/cByJ mice. In contrast, in the hardier C57BL/6ByJ mice the acute stressor increased ir-CRHr in portions of the OFC, whereas a chronic stressor tended to reduce ir-CRHr. However, whereas the acute stressor did not influence CRH 1 mRNA expression, the chronic stressor increased CRH 1 mRNA expression in both mouse strains. The CRH 2 expression appeared in low abundance in both strains and was unaltered by the stressor. In addition to the OFC variations, quantitative immunohistochemistry indicated that the chronic stressor treatment increased CRH immunoreactivity in the median eminence of C57BL/6ByJ mice, but co-expression of CRH and arginine vasopressin (AVP) immunoreactivity was not provoked by the stressors. The data support the view that stressors provoke marked variations of ir-CRHr in the OFC that might contribute to the differential anxiety/depression-like profiles ordinarily apparent in the stressor-vulnerable and -resilient mouse strains.
Glucocorticoids, Transmitters and Stress
British Journal of Psychiatry, 1992
Many kinds of stress stimulate the neuroendocrine systems controlling catecholamine and glucocorticoid secretion. Stress-induced stimulation of CRF-containing neurons appears to be mediated by serotonergic, noradrenergic, and possibly other neuronal pathways. Stress can alter various neurobiological and endocrine functions, two essential components of the neuroendocrine responses being release of adrenalin from chromaffin cells of the adrenal medulla and secretion of glucocorticoids from adrenocortical cells. Activation of adrenal steroid secretion is mainly by a reflex activation of hypothalamic neurons, which stimulate ACTH secretion from the anterior pituitary. While the neuropeptide CRF plays a major role in the neuroendocrine response to stress, the neuronal signals which are responsible for the regulation of CRF neurons have not been completely elucidated. A number of other regulatory substances may also participate, alone or with CRF, in the control of ACTH secretion by pituitary corticotrophs, and there is increasing evidence that classical neurotransmitters or neuropeptides may act directly on adrenocortical cells to modulate corticosteroid secretion. We review the neuronal, neuroendocrine, and humoral pathways which participate in the regulation of stressinduced corticosteroid secretion, and present preliminary data on the effect of the tricyclic antidepressant, tianeptine in the response of the HPA axis to stress.